tbuckley/cabot-search huggingface dataset:
Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis
Authors: Wei Shen, Michael S. Middleton, Guilherme M. Cunha, Timoteo I. Delgado, Tanya Wolfson, Anthony Gamst, Kathryn J. Fowler, Adina Alazraki, Andrew T. Trout, Michael A. Ohliger, Shetal N. Shah, Mustafa R. Bashir, David E. Kleiner, Rohit Loomba, Brent A. Neuschwander-Tetri, Arun J. Sanyal, Jane Zhou, Claude B. Sirlin, Joel E. Lavine
Journal: Journal of Hepatology (2022)
Integration of ER protein quality control mechanisms defines β cell function and ER architecture
Authors: Neha Shrestha, Mauricio Torres, Jason Zhang, You Lu, Leena Haataja, Rachel B. Reinert, Jeffrey Knupp, Yu-Jie Chen, Gunes Parlakgul, Ana Paula Arruda, Billy Tsai, Peter Arvan, Ling Qi
Journal: Journal of Clinical Investigation (2022)

Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.
Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance
Authors: Yingfu Jiao, Po Gao, Li Dong, Xiaowei Ding, Youqiang Meng, Jiahong Qian, Ting Gao, Ruoxi Wang, Tao Jiang, Yunchun Zhang, Dexu Kong, Yi Wu, Sihan Chen, Saihong Xu, Dan Tang, Ping Luo, Meimei Wu, Li Meng, Daxiang Wen, Changhao Wu, Guohua Zhang, Xueyin Shi, Weifeng Yu, Weifang Rong
Journal: Journal of Clinical Investigation (2022)

The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein–coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor–mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.
Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine
Authors: Karama Asleh, Ana Lluch, Angela Goytain, Carlos Barrios, Xue Q. Wang, Laura Torrecillas, Dongxia Gao, Manuel Ruiz-Borrego, Samuel Leung, José Bines, Ángel Guerrero-Zotano, Jose Ángel García-Sáenz, Juan Miguel Cejalvo, Jesus Herranz, Roberto Torres, Juan de la Haba-Rodriguez, Francisco Ayala, Henry Gómez, Federico Rojo, Torsten O. Nielsen, Miguel Martin
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial. Experimental Design: Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival. Results: Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07–0.54; P &amp;lt; 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63–1.28; P = 0.55; Pinteraction&amp;lt;0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype. Conclusions: In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine.
<i>NBN</i> Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and <i>In Vitro</i> DNA Damage Response Defects
Authors: Sami Belhadj, Aliya Khurram, Chaitanya Bandlamudi, Guillermo Palou-Márquez, Vignesh Ravichandran, Zoe Steinsnyder, Temima Wildman, Amanda Catchings, Yelena Kemel, Semanti Mukherjee, Benjamin Fesko, Kanika Arora, Miika Mehine, Sita Dandiker, Aalin Izhar, John Petrini, Susan Domchek, Katherine L. Nathanson, Jamie Brower, Fergus Couch, Zsofia Stadler, Mark Robson, Michael Walsh, Joseph Vijai, Michael Berger, Fran Supek, Rachid Karam, Sabine Topka, Kenneth Offit
Journal: Clinical Cancer Research (2022)

To explore the role of NBN as a pan-cancer susceptibility gene.
Mechanisms of MCL-1 Protein Stability Induced by MCL-1 Antagonists in B-Cell Malignancies
Authors: Shady I. Tantawy, Aloke Sarkar, Stefan Hubner, Zhi Tan, William G. Wierda, Abdelraouf Eldeib, Shuxing Zhang, Steven Kornblau, Varsha Gandhi
Journal: Clinical Cancer Research (2022)

Several MCL-1 inhibitors (MCL-1i), including AMG-176 and AZD5991, have shown promise in preclinical studies and are being tested for the treatment of hematologic malignancies. A unique feature of these agents is induction and stability of Mcl-1 protein; however, the precise mechanism is unknown. We aim to study the mechanism of MCL-1i-induced Mcl-1 protein stability.Using several B-cell leukemia and lymphoma cell lines and primary chronic lymphocytic leukemia (CLL) lymphocytes, we evaluated molecular events associated with Mcl-1 protein stability including protein half-life, reverse-phase protein array, protein-protein interaction, phosphorylation, ubiquitination, and de-ubiquitination, followed by molecular simulation and modeling.Using both in vivo and in vitro analysis, we demonstrate that MCL-1i-induced Mcl-1 protein stability is predominantly associated with defective Mcl-1 ubiquitination and concurrent apoptosis induction in both cell lines and primary CLL subjects. These MCL1i also induced ERK-mediated Mcl-1Thr163 phosphorylation, which partially contributed to Mcl-1 stability. Disruption of Mcl-1:Noxa interaction followed by Noxa degradation, enhanced Mcl-1 de-ubiquitination by USP9x, and Mule destabilization are the major effects of these inhibitors. However, unlike other BH3 proteins, Mule:Mcl-1 interaction was unaffected by MCL-1i. WP1130, a global deubiquitinase (DUB) inhibitor, abrogated Mcl-1 induction reaffirming a critical role of DUBs in the observed Mcl-1 protein stability. Further, in vitro ubiquitination studies of Mcl-1 showed distinct difference among these inhibitors.We conclude that MCL-1i blocked Mcl-1 ubiquitination via enhanced de-ubiquitination and dissociation of Mcl-1 from Noxa, Bak and Bax, and Mule de-stabilization. These are critical events associated with increased Mcl-1 protein stability with AMG-176 and AZD5991.
Sleep-related attentional and interpretive-bias in insomnia: A systematic review and meta-analysis
Authors: Umair Akram, Nicola Barclay, Bronwyn Milkins, Jodie Stevenson, Maria Gardani
Journal: Sleep Medicine Reviews (2022)

Cognitive models of insomnia highlight internal and external cognitive-biases for sleep-related "threat" in maintaining the disorder. This systematic review of the sleep-related attentional and interpretive-bias literature includes meta-analytic calculations of each construct. Searches identified N = 21 attentional-bias and N = 8 interpretive-bias studies meeting the inclusion/exclusion criteria. Seventeen attentional-bias studies compared normal-sleepers and poor-sleepers/insomnia patients. Using a random effects model, meta-analytic data based on standardized mean differences of attentional-bias studies determined the weighted pooled effect size to be moderate at 0.60 (95%CI:0.26-0.93). Likewise, seven of eight interpretive-bias studies involved group comparisons. Meta-analytic data determined the weighted pooled effect size as moderate at .44 (95%CI:0.19-0.69). Considering these outcomes, disorder congruent cognitive-biases appear to be a key feature of insomnia. Despite statistical support, absence of longitudinal data limits causal inference concerning the relative role cognitive-biases in the development and maintenance of insomnia. Methodological factors pertaining to task design, sample and stimuli are discussed in relation to outcome variation. Finally, we discuss the next steps in advancing the understanding of sleep-related biases in insomnia.
Predicting Molecular Subtype and Survival of Rhabdomyosarcoma Patients Using Deep Learning of H&amp;E Images: A Report from the Children's Oncology Group
Authors: David Milewski, Hyun Jung, G. Thomas Brown, Yanling Liu, Ben Somerville, Curtis Lisle, Marc Ladanyi, Erin R. Rudzinski, Hyoyoung Choo-Wosoba, Donald A. Barkauskas, Tammy Lo, David Hall, Corinne M. Linardic, Jun S. Wei, Hsien-Chao Chou, Stephen X. Skapek, Rajkumar Venkatramani, Peter K. Bode, Seth M. Steinberg, George Zaki, Igor B. Kuznetsov, Douglas S. Hawkins, Jack F. Shern, Jack Collins, Javed Khan
Journal: Clinical Cancer Research (2022)

Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS.Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998-2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data.The trained CNN could accurately classify alveolar RMS, a high-risk subtype associated with PAX3/7-FOXO1 fusion genes, with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67, and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63, respectively. Remarkably, CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification.This study demonstrates that high-risk features, including those associated with certain mutations, can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma, which will be tested in prospective COG clinical trials.
Gut microbiota as non-invasive diagnostic and prognostic biomarkers for natural killer/T-cell lymphoma
Authors: Zhuangzhuang Shi, Guoru Hu, Min W Li, Lei Zhang, Xin Li, Ling Li, Xinhua Wang, Xiaorui Fu, Zhenchang Sun, Xudong Zhang, Li Tian, Zhaoming Li, Wei-Hua Chen, Mingzhi Zhang
Journal: Gut (2022)
<scp>CAR</scp> T cell‐driven cerebrospinal fluid cytokine storm with confounding neurological picture in chemorefractory primary cardiac lymphoma
Authors: Vincenzo Maria Perriello, Lorenza Falini, Loredana Ruggeri, Alessandra Innocente, Stelvio Ballanti, Cinzia Costa, Massimiliano Di Filippo, Marco Gargaro, Francesca Fallarino, Brunangelo Falini
Journal: American Journal of Hematology (2022)
Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer
Authors: Wen Chen, Kun Shi, Jie Liu, Peipei Yang, Ruxia Han, Meng Pan, Liping Yuan, Chao Fang, Yongyang Yu, Zhiyong Qian
Journal: Bioactive Materials (2022)

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, posing a severe threat to human health. Surgical resection remains the most preferred option for gastric cancer treatment. However, for advanced gastric cancer, the curative effect of surgical resection is usually limited by the local recurrence, peritoneal carcinomatosis, or distal metastasis. Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection. Here, we designed a 5-fluorouracil (5-FU) and cis-platinum (DDP) co-delivery system based on a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) for intraoperative adjuvant combination chemotherapy of gastric cancer. This 5-FU + DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo. A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU + DDP/PLEL were observed against gastric cancer MKN45-luc cells. After intraperitoneal injection, the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model. The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well. What's more, we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer, in which the intraoperative administration of 5-FU + DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors, resulting in an extended lifetime. Hence, this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer, that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.
Probing the dynamic RNA structurome and its functions
Authors: Robert C. Spitale, Danny Incarnato
Journal: Nature Reviews Genetics (2022)

RNA is a key regulator of almost every cellular process, and the structures adopted by RNA molecules are thought to be central to their functions. The recent fast-paced evolution of high-throughput sequencing-based RNA structure mapping methods has enabled the rapid in vivo structural interrogation of entire cellular transcriptomes. Collectively, these studies are shedding new light on the long underestimated complexity of the structural organization of the transcriptome — the RNA structurome. Moreover, recent analyses are challenging the view that the RNA structurome is a static entity by revealing how RNA molecules establish intricate networks of alternative intramolecular and intermolecular interactions and that these ensembles of RNA structures are dynamically regulated to finely tune RNA functions in living cells. This new understanding of how RNA can shape cell phenotypes has important implications for the development of RNA-targeted therapeutic strategies. In this Review, Spitale and Incarnato discuss how the application of sequencing-based RNA structure mapping methods to entire transcriptomes in living cells is providing insight into the RNA structurome, the dynamics of RNA ensembles and how RNA structure regulates cellular processes.
Tuning the 3D microenvironment of reprogrammed tubule cells enhances biomimetic modeling of polycystic kidney disease
Authors: Roman Pichler, Ludovica Rizzo, Kevin Tröndle, Michaela Bühler, Hanna Brucker, Anna-Lena Müller, Kelli Grand, Silvia Farè, Amandine Viau, Michael M. Kaminski, E. Wolfgang Kuehn, Fritz Koch, Stefan Zimmermann, Peter Koltay, Soeren S. Lienkamp
Journal: Biomaterials (2022)

Renal tubular cells frequently lose differentiation markers and physiological properties when propagated in conventional cell culture conditions. Embedding cells in 3D microenvironments or controlling their 3D assembly by bioprinting can enhance their physiological properties, which is beneficial for modeling diseases in vitro. A potential cellular source for modeling renal tubular physiology and kidney diseases in vitro are directly reprogrammed induced renal tubular epithelial cells (iRECs). iRECs were cultured in various biomaterials and as bioprinted tubular structures. They showed high compatibility with the embedding substrates and dispensing methods. The morphology of multicellular aggregates was substantially influenced by the 3D microenvironment. Transcriptomic analyses revealed signatures of differentially expressed genes specific to each of the selected biomaterials. Using a new cellular model for autosomal-dominant polycystic kidney disease, Pkd1−/− iRECs showed disrupted morphology in bioprinted tubules and a marked upregulation of the Aldehyde dehydrogenase 1a1 (Aldh1a1). In conclusion, 3D microenvironments strongly influence the morphology and expression profiles of iRECs, help to unmask disease phenotypes, and can be adapted to experimental demands. Combining a direct reprogramming approach with appropriate biomaterials will facilitate construction of biomimetic kidney tubules and disease models at the microscale.
Natural killer T cells and other innate-like T lymphocytes as emerging platforms for allogeneic cancer cell therapy
Authors: Amy N. Courtney, Gengwen Tian, Leonid S. Metelitsa
Journal: Blood (2022)

T cells expressing chimeric antigen receptors (CARs) have achieved major clinical success in patients with hematologic malignancies. However, these treatments remain largely ineffective for solid cancers and require significant time and resources to be manufactured in an autologous setting. Developing alternative immune effector cells as cancer immunotherapy agents that can be employed in allogeneic settings is crucial for the advancement of cell therapy. Unlike T cells, Vα24-invariant natural killer T cells (NKTs) are not alloreactive and can therefore be generated from allogeneic donors for rapid infusion into numerous patients without the risk of graft-versus-host disease. Additionally, NKT cells demonstrate inherent advantages over T-cell products, including the ability to traffic to tumor tissues, target tumor-associated macrophages, transactivate NK cells, and cross-prime tumor-specific CD8 T cells. Both unmodified NKTs, which specifically recognize CD1d-bound glycolipid antigens expressed by certain types of tumors, and CAR-redirected NKTs are being developed as the next generation of allogeneic cell therapy products. In this review, we describe studies on the biology of NKTs and other types of innate-like T cells and summarize the clinical experiences of unmodified and CAR-redirected NKTs, including recent interim reports on allogeneic NKTs.
Lineage abundance estimation for SARS-CoV-2 in wastewater using transcriptome quantification techniques
Authors: Jasmijn A. Baaijens, Alessandro Zulli, Isabel M. Ott, Ioanna Nika, Mart J. van der Lugt, Mary E. Petrone, Tara Alpert, Joseph R. Fauver, Chaney C. Kalinich, Chantal B. F. Vogels, Mallery I. Breban, Claire Duvallet, Kyle A. McElroy, Newsha Ghaeli, Maxim Imakaev, Malaika F. Mckenzie-Bennett, Keith Robison, Alex Plocik, Rebecca Schilling, Martha Pierson, Rebecca Littlefield, Michelle L. Spencer, Birgitte B. Simen, Ahmad Altajar, Anderson F. Brito, Anne E. Watkins, Anthony Muyombwe, Caleb Neal, Chen Liu, Christopher Castaldi, Claire Pearson, David R. Peaper, Eva Laszlo, Irina R. Tikhonova, Jafar Razeq, Jessica E. Rothman, Jianhui Wang, Kaya Bilguvar, Linda Niccolai, Madeline S. Wilson, Margaret L. Anderson, Marie L. Landry, Mark D. Adams, Pei Hui, Randy Downing, Rebecca Earnest, Shrikant Mane, Steven Murphy, William P. Hanage, Nathan D. Grubaugh, Jordan Peccia, Michael Baym
Journal: Genome biology (2022)

Abstract Effectively monitoring the spread of SARS-CoV-2 mutants is essential to efforts to counter the ongoing pandemic. Predicting lineage abundance from wastewater, however, is technically challenging. We show that by sequencing SARS-CoV-2 RNA in wastewater and applying algorithms initially used for transcriptome quantification, we can estimate lineage abundance in wastewater samples. We find high variability in signal among individual samples, but the overall trends match those observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in mutant prevalence in situations where clinical sequencing is unavailable.
Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial
Authors: Tianyi Wang, Yanjing Tang, Jiaoyang Cai, Xinyu Wan, Shaoyan Hu, Xiaoxi Lu, Zhiwei Xie, Xiaohong Qiao, Hui Jiang, Jingbo Shao, Fan Yang, Hong Ren, Qing Cao, Juan Qian, Jian Zhang, Kang An, Jianmin Wang, Chengjuan Luo, Huanhuan Liang, Yan Miao, Yani Ma, Xiang Wang, Lixia Ding, Lili Song, Hailong He, Wenhua Shi, Peifang Xiao, Xiaomin Yang, Jing Yang, Wenjie Li, Yiping Zhu, Ningling Wang, Longjun Gu, Qimin Chen, Jingyan Tang, Jun J. Yang, Cheng Cheng, Wing Leung, Jing Chen, Jun Lu, Benshang Li, Ching-Hon Pui
Journal: Journal of Clinical Oncology (2022)

We determined the safety and efficacy of coadministration of CD19- and CD22-chimeric antigen receptor (CAR) T cells in patients with refractory disease or high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia.
Design, development and clinical translation of CriPec®-based core-crosslinked polymeric micelles
Authors: Cristianne J.F. Rijcken, Federica De Lorenzi, Ilaria Biancacci, Rob G.J.M. Hanssen, Marielle Thewissen, Qizhi Hu, Florence Atrafi, Rob M.J. Liskamp, Ron H.J. Mathijssen, Iris H.C. Miedema, C. Willemien Menke - van der Houven van Oordt, Guus A.M.S. van Dongen, Danielle J. Vugts, Matt Timmers, Wim E. Hennink, Twan Lammers
Journal: Advanced Drug Delivery Reviews (2022)